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Hepcidin and 1,25(OH)2D3 effectively restore Ca2+ transport in {beta}-thalassemic mice: reciprocal phenomenon of Fe2+ and Ca2+ absorption

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AJP Endocrinology and Metabolism

Published online on

Abstract

Previously, β-thalassemia, an inherited anemic disorder with iron overload caused by loss-of-function mutation of β-globin gene, has been reported to induce osteopenia and impaired whole-body calcium metabolism, but the pathogenesis of aberrant calcium homeostasis remains elusive. Herein, we investigated how β-thalassemia impaired intestinal calcium absorption and whether it could be restored by administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or hepcidin, the latter of which was liver-derived antagonist of intestinal iron absorption. The results showed that, in hemizygous β-globin knockout (BKO) mice, the duodenal calcium transport was lower than that in wild-type littermate, and severity was especially pronounced in female mice. Both active and passive duodenal calcium fluxes in BKO mice were found to be less than those in normal mice, which could be restored by 7-day 1,25(OH)2D3 treatment. Such the 1,25(OH)2D3-induced calcium transport was diminished by inhibitors of calcium transporters, e.g., L-type calcium channel, NCX1, PMCA1b, as well as vesicular transport inhibitor. Interestingly, the duodenal calcium transport exhibited an inverse correlation with transepithelial iron transport, which was markedly enhanced in thalassemic mice. Thus, 3-day subcutaneous hepcidin injection and acute direct hepcidin exposure in Ussing chamber were capable of restoring the thalassemia-associated impairment of calcium transport; however, the positive effect of hepcidin on calcium transport was completely blocked by proteasome inhibitors, MG132 and bortezomib. In conclusion, 1,25(OH)2D3 impairment of calcium absorption. Our study has, therefore, shed light on the development of treatment strategy to rescue calcium dysregulation in β-thalassemia.